System and Method of Loading and Detecting Beneficial Agent on a Prosthesis

ABSTRACT

An interventional device for delivery of beneficial agent to a lumen and methods of loading and manufacture of the same, which include a prosthesis loaded with beneficial agent to provide a controlled dosage concentration of beneficial agent to the lumen. The beneficial agent is loaded onto the prosthesis by a fluid-dispenser having a dispensing element capable of dispensing the beneficial agent in discrete droplets, each droplet having a controlled trajectory. The method of loading beneficial agent includes dispensing beneficial agent in a raster format and/or an off-axis format along a dispensing path.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/465,396filed Aug. 17, 2006, which is a divisional of application Ser. No.10/703,820, filed Nov. 7, 2003, now U.S. Pat. No. 7,208,190, whichclaims the benefit of Provisional Application Nos. 60/424,574;60/424,575; 60/424,576; 60/424,577; and 60/424,607, each of theprovisional applications filed on Nov. 7, 2002. Each of theabove-identified applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a method and system for loading beneficialagent onto a prosthesis using a fluid-dispenser having a dispensingelement capable of dispensing beneficial agent in discrete droplets,each droplet having a controlled trajectory. The method in particularrelates to a method of dispensing beneficial agent in a raster formatand/or an off-axis format along a dispensing path.

2. Description of Related Art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. This procedure generally entails introducing acatheter assembly into the cardiovascular system of a patient via thebrachial or femoral artery, and advancing the catheter assembly throughthe coronary vasculature until a balloon portion thereon is positionedacross an occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to radially compress againstthe atherosclerotic plaque of the lesion to remodel the vessel wall.Subsequently, the balloon is deflated to allow the catheter assembly tobe withdrawn from the vasculature.

While PCTA is widely used, it suffers from two unique problems. First,the blood vessel may suffer acute occlusion immediately after or withinthe initial hours after the dilation procedure. Such occlusion isreferred to as “abrupt closure.” Abrupt closure occurs in approximatelyfive percent of cases in which PTCA is employed. The primary mechanismsof abrupt closures are believed to be elastic recoil, arterialdissection and/or thrombosis. The second problem associated with thisprocedure is the re-narrowing of an artery after an initially successfulangioplasty. This re-narrowing is referred to as “restenosis,” whichtypically occurs within the first six months after angioplasty.Restenosis is believed to be due to, among other things, theproliferation and migration of cellular components from the arterialwall, as well as through geometric changes in the arterial wall referredto as “remodeling.”

To reduce occlusion of the artery, and the development of thrombosisand/or restenosis, an expandable interventional device or prosthesis,one example of which includes a stent, is implanted in the lumen tomaintain the vascular patency. Additionally, to better effectuate thetreatment of such vascular disease, it is preferable to load anintraluminal device or prosthesis with one or more beneficial agents,such as antiproliferatives, for delivery to a lumen. One commonlyapplied technique for the local delivery of a drug is through the use ofa polymeric carrier coated onto the surface of a stent, as disclosed inBerg et al., U.S. Pat. No. 5,464,650, the disclosure of which isincorporated herein by reference thereto. Such conventional methods andproducts generally have been considered satisfactory for their intendedpurpose. However, some problems associated with such drug elutinginterventional devices is the variability in drug loading across aninterventional device, as well as the variability in drug concentrationfrom device to device. Other disadvantages include the inability totightly control and maintain drug concentration, the inability to verifydrug distribution or drug loading on any given device, the inability tovary drug distribution in a controlled and predetermined manner toeffect a more desirable drug loading profile, the inability to loaddifferent, and in particular incompatible or reactive drugs onto thesame surface of a device, and the difficulty in controlling the localareal density of beneficial agent that is delivered to the lumen,particularly if the interventional device is an overlapping orbifurcated device coated with beneficial agent.

As evident from the related art, conventional methods of loadinginterventional devices with beneficial agents, such as drugs, oftenrequires coating the entire prosthesis with a polymer capable ofreleasing therapeutic drugs, as disclosed in Campbell, U.S. Pat. No.5,649,977 and Dinh et al., U.S. Pat. No. 5,591,227, the disclosures ofwhich are incorporated herein by reference thereto. Because certaininterventional devices may have a varied surface area along its length,such conventional loading techniques results in unintentional orundesirable dosage variations. Additionally, if it is desired tosuperimpose two or more conventional-loaded prostheses, such as withnested stents or bifurcated stents, the total dosage of beneficial agentto the lumen will exceed the nominal or desired dosage. Another drawbackof the conventional methods of loading interventional devices withbeneficial agents is the lack of selective dosing, such as providingvarious beneficial agents or various concentrations of the samebeneficial agent at different locations on a prosthesis to effect atherapy at specific targeted sites.

Thus, there remains a need for efficient and economic methods forcontrolling the loading of beneficial agent onto a prosthesis so as toprovide an interventional device having a varied distribution profile ofbeneficial agent to effect therapy at targeted locations of the lumen.Additionally, there is a need for an interventional device capable ofproviding combination therapy of two or more beneficial agents loaded ondifferent surfaces of a prosthesis to effectuate systemic release aswell as release to the wall of the lumen. Further, a need exists for theloading of incompatible beneficial agents onto the same surface of aprosthesis. The advantages of the present invention satisfy theaforementioned needs.

SUMMARY OF THE INVENTION

The purpose and advantages of the present invention will be set forth inand will become apparent from the description that follows, as well aswill be learned by practice of the invention.

Additionally, advantages of the invention will be realized and attainedby the methods and systems particularly pointed out in the writtendescription and claims hereof, as well as from the appended drawings.

In aspects of the present invention, a system for loading beneficialagent onto a prosthesis for delivery within a lumen comprises a holder,a fluid-dispenser, a driver, a controller, and a beneficial agentdetector. The holder is for supporting a prosthesis to be deployedwithin a lumen. The fluid-dispenser has a dispensing element capable ofdispensing beneficial agent in discrete droplets, each droplet having acontrolled trajectory, the dispensing element and the holder beingmovable relative to each other, said dispensing element being positionedat a distance sufficient such that the dispensing element and prosthesisin the holder are separated by a distance that avoids simultaneouscontact of the dispensing element and prosthesis by a discrete droplet.The driver is for creating relative movement between the dispensingelement and the holder. The controller is in communication with thedriver to define a dispensing path for dispensing discrete droplets ofbeneficial agent with the controlled trajectory in a raster format, thecontroller is also in communication with the dispensing element toselectively dispense beneficial agent from the dispensing element to apredetermined portion of a prosthesis supported by the holder along thedispensing path. The beneficial agent detector is in communication withthe controller configured to determine an amount of beneficial agentloaded on a prosthesis, the beneficial agent detector being configuredto be capable of detecting charge build-up on or current flow from theprosthesis to determine a corresponding amount of beneficial agentloaded to the prosthesis.

In other aspects, the controlled trajectory is controlled by thecontroller so as to not intersect a central axis of the prosthesis.

In other aspects, the beneficial agent detector is configured to becapable of detecting the number of discrete droplets dispensed from thefluid-dispenser onto the prosthesis to determine a corresponding amountof beneficial agent loaded to the prosthesis.

In aspects of the present invention, a method for loading beneficialagent onto a prosthesis for delivery within a lumen comprisingsupporting on a holder a prosthesis to be deployed within a lumen. Themethod further comprises dispensing from a dispensing element abeneficial agent in discrete droplets, each droplet having a controlledtrajectory. The method further comprises positioning the dispensingelement at a distance from the holder, the distance sufficient to avoidsimultaneous contact of the dispensing element and prosthesis by thedispensed discrete droplets. The method further comprises moving theholder and the dispensing element relative to each other, the movementdefining a dispensing path for the dispensing of the discrete dropletsof the beneficial agent with the controlled trajectory in a rasterformat. The method further comprises determining an amount of thebeneficial agent dispensed on the prosthesis.

In further aspects, the determining of the amount of the beneficialagent dispensed on the prosthesis includes detecting a charge build-upon or current flow from the prosthesis.

In further aspects, the determining of the amount of the beneficialagent dispensed on the prosthesis includes detecting the number ofdiscrete droplets dispensed from the dispensing element onto theprosthesis.

In further aspects, the controlled trajectory does not intersect acentral axis of the prosthesis.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and are intended toprovide further explanation of the invention claimed.

The accompanying Figures, which are incorporated in and constitute partof this specification, are included to illustrate and provide a furtherunderstanding of the method and system of the invention. Together withthe description, the Figures serve to explain the principles of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a-1 c are schematic representations of a prosthesis loaded withbeneficial agent having a first portion and a second portion havingdifferent local areal densities of beneficial agent in accordance withthe present invention, and graphs depicting corresponding areal density.

FIG. 2 is a schematic representation of a first prosthesis and a secondprosthesis configured to define a nested interventional device, each atleast partially loaded with beneficial agent in accordance with thepresent invention.

FIG. 3 is a schematic representation of the first prosthesis and secondprosthesis of FIG. 2, deployed in overlapping relationship to provide acontrolled local areal density across the length of the interventionaldevice.

FIG. 4 is a schematic representation of a first prosthesis and secondprosthesis configured to define a bifurcated interventional device, eachat least partially loaded with beneficial agent in accordance with thepresent invention.

FIG. 5 is a schematic representation of the first prosthesis and secondprosthesis of FIG. 4, deployed in an overlapping relationship to providea bifurcated interventional device having a controlled local arealdensity across a length of the interventional device.

FIG. 6 is a schematic representation of an interventional device, andFIG. 6 a is a detail schematic depicting a raster format for loadingbeneficial agent thereon.

FIG. 7 is a schematic representation of an embodiment of the system ofthe present invention.

FIGS. 8 a-8 d are schematic representations of an “off-axis” dispensingmethod at various cross-sections of the device of FIG. 6.

FIG. 9 is a schematic representation of another embodiment of the systemof the present invention.

FIG. 10 is a schematic representation of discrete droplets loaded in anoverlapping manner.

FIG. 11 is a schematic representation of a method of loading beneficialagent on an inner surface of an interventional device.

FIG. 12 is a schematic representation of the cross-section of thestructural element of a prosthesis having a cavity therein.

FIG. 13 is a schematic representation of the holding tool assembly ofthe system of the invention, FIG. 13 a is a detail schematic depictingthe holding tool assembly including the spindle.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Reference will now be made in detail to the present preferredembodiments of the method and system for loading beneficial agent onto aprosthesis, and the interventional devices loaded with beneficial agent.Wherever possible, the same reference characters will be used throughoutthe drawings to refer to the same or like parts.

In accordance with the present invention, an interventional device isprovided for delivery of beneficial agent within a lumen. Particularly,the present invention is suited for providing an interventional devicehaving a controlled areal density of beneficial agent for the treatmentand prevention of vascular or other intraluminal diseases. Generally,“controlled areal density” is understood to mean a known orpredetermined amount of beneficial agent, either by weight or volume,over a unit surface area of the interventional device.

As used herein “interventional device” refers broadly to any devicesuitable for intraluminal delivery or implantation. For purposes ofillustration and not limitation, examples of such interventional devicesinclude stents, grafts, stent-grafts, filters, and the like. As is knownin the art, such devices may comprise one or more prostheses, eachhaving a first cross-sectional dimension or profile for the purpose ofdelivery and a second cross-sectional dimension or profile afterdeployment. Each prosthesis may be deployed by known mechanicaltechniques such as balloon expansion deployment techniques, or byelectrical or thermal actuation, or self-expansion deploymenttechniques, as well known in the art. Examples of such for purpose ofillustration include U.S. Pat. No. 4,733,665 to Palmaz; U.S. Pat. No.6,106,548 to Roubin et al.; U.S. Pat. No. 4,580,568 to Gianturco; U.S.Pat. No. 5,755,771 to Penn et al.; and U.S. Pat. No. 6,033,434 toBorghi, all of which are incorporated herein by reference.

For purposes of explanation and illustration, and not limitation, anexemplary embodiment of the interventional device in accordance with theinvention is shown schematically in FIG. 1 a. In accordance with oneaspect of the invention, as shown schematically in FIG. 1, theinterventional device generally includes a prosthesis 10 loaded withbeneficial agent to provide a local areal density of beneficial agentacross a length of the interventional device. Particularly, as embodiedherein the prosthesis may be a stent, a graft, a stent-graft, a filter,or the like, as previously noted, for intravascular or coronary deliveryand/or implantation. However, the prosthesis may be any type ofintraluminal member capable of being loaded with beneficial agent.

The prosthesis can be in an expanded or unexpanded state during theloading of beneficial agent. The underlying structure of the prosthesiscan be virtually any structural design and the prosthesis can becomposed any suitable material such as, but not limited to, stainlesssteel, “MP35N,” “MP20N,” elastinite (Nitinol), tantalum, nickel-titaniumalloy, platinum-iridium alloy, gold, magnesium, polymer, ceramic,tissue, or combinations thereof “MP35N” and “MP20N” are understood to betrade names for alloys of cobalt, nickel, chromium and molybdenumavailable from Standard Press Steel Co., Jenkintown, Pa. “MP35N”consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.“MP20N” consists of 50% cobalt, 20% nickel, 20% chromium and 10%molybdenum. The prosthesis can be made from bioabsorbable or biostablepolymers. In some embodiments, the surface of the prosthesis can includeone or more reservoirs or cavities formed therein, as described furtherbelow.

The prosthesis can be fabricated utilizing any number of methods knownin the art. For example, the prosthesis can be fabricated from a hollowor formed tube that is machined using lasers, electric dischargemilling, chemical etching or other known techniques. Alternatively, theprosthesis can be fabricated from a sheet that is rolled into a tubularmember, or formed of a wire or filament construction as known in theart.

As noted above, the prosthesis is at least partially loaded withbeneficial agent (10 a, 10 b, 10 c). “Beneficial agent” as used herein,refers to any compound, mixture of compounds, or composition of matterconsisting of a compound, which produces a beneficial or useful result.The beneficial agent can be a polymer, a marker, such as a radiopaquedye or particles, or can be a drug, including pharmaceutical andtherapeutic agents, or an agent including inorganic or organic drugswithout limitation. The agent or drug can be in various forms such asuncharged molecules, components of molecular complexes,pharmacologically-acceptable salts such as hydrochloride, hydrobromide,sulfate, laurate, palmitate, phosphate, nitrate, borate, acetate,maleate, tartrate, oleate, and salicylate.

An agent or drug that is water insoluble can be used in a form that is awater-soluble derivative thereof to effectively serve as a solute, andon its release from the device, is converted by enzymes, hydrolyzed bybody pH, or metabolic processes to a biologically active form.Additionally, the agents or drug formulations can have various knownforms such as solutions, dispersions, pastes, particles, granules,emulsions, suspensions and powders. The drug or agent may or may not bemixed with polymer or a solvent as desired.

For purposes of illustration and not limitation, the drug or agent caninclude antithrombotics, anticoagulants, antiplatelet agents,thrombolytics, antiproliferatives, anti-inflammatories, agents thatinhibit hyperplasia, inhibitors of smooth muscle proliferation,antibiotics, growth factor inhibitors, or cell adhesion inhibitors.Other drugs or agents include but are not limited to antineoplastics,antimitotics, antifibrins, antioxidants, agents that promote endothelialcell recovery, antiallergic substances, radiopaque agents, viralvectors, antisense compounds, oligionucleotides, cell permeationenhancers, angiogenesis agents, and combinations thereof.

Examples of such antithrombotics, anticoagulants, antiplatelet agents,and thrombolytics include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapriprost, prostacyclinand prostacylin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa (plateletmembrane receptor antagonist antibody), recombinant hirudin, andthrombin inhibitors such as ANGIOMAX™, from Biogen, Inc., Cambridge,Mass.; and thrombolytic agents, such as urokinase, e.g., ABBOKINASE™from Abbott Laboratories Inc., North Chicago, Ill., recombinanturokinase and pro-urokinase from Abbott Laboratories Inc., tissueplasminogen activator (ALTEPLASE™ from Genentech, South San Francisco,Calif. and tenecteplase (TNK-tPA).

Examples of such cytostatic or antiproliferative agents includerapamycin and its analogs such as everolimus, ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3Hpyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone,which is disclosed in U.S. Pat. No. 6,015,815, U.S. Pat. No. 6,329,386,US Publication 2003/129215, filed on Sep. 6, 2002, and US Publication2002/123505, filed Sep. 10, 2001, the disclosures of which are eachincorporated herein by reference thereto, tacrolimus and pimecrolimus,angiopeptin, angiotensin converting enzyme inhibitors such as captopril,e.g, CAPOTEN® and CAPOZIDE® from Bristol-Myers Squibb Co., Stamford,Conn., cilazapril or lisinopril, e.g., PRINIVIL® and PRINZIDE® fromMerck & Co., Inc., Whitehouse Station, N.J.; calcium channel blockerssuch as nifedipine, amlodipine, cilnidipine, lercanidipine, benidipinie,trifluperazine, diltiazem and verapamil, fibroblast growth factorantagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin, e.g. MEVACOR® from Merck & Co., Inc., Whitehouse Station,N.J. In addition, topoisomerase inhibitors such as etoposide andtopotecan, as well as antiestrogens such as tamoxifen may be used.

Examples of such anti-inflammatories include colchicine andglucocorticoids such as betamethasone, cortisone, dexamethasone,budesonide, prednisolone, methylprednisolone and hydrocortisone.Non-steroidal anti-inflammatory agents include flurbiprofen, ibuprofen,ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen,indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamicacid, piroxicam and phenylbutazone.

Examples of such antineoplastics include alkylating agents such asaltretamine, bendamucine, carboplatin, carmustine, cisplatin,cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine,prednimustine, and treosulfin, antimitotics such as vincristine,vinblastine, paclitaxel, e.g., TAXOL® by Bristol-Myers Squibb Co.,Stamford, Conn., docetaxel, e.g., TAXOTERE® from Aventis S.A.,Frankfort, Germany, antimetabolites such as methotrexate,mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine,and fluorouracil, and antibiotics such as doxorubicin hydrochloride,e.g., ADRIAMYCIN® from Pharmacia & Upjohn, Peapack, N.J., and mitomycin,e.g., MUTAMYCIN® from Bristol-Myers Squibb Co., Stamford, Conn., agentsthat promote endothelial cell recovery such as Estradiol.

Additional drugs which may be utilized in this application includedexamethasone; fenofibrate; inhibitors of tyrosine kinase such asRPR-101511A; PPAR-alpha agonists such as TRICOR™ formulation from AbbottLaboratories Inc., North Chicago, Ill.; endothelin receptor antagonistssuch as ABT-627 having general formula C₂₉H₃₈N₂O₆.ClH, and the followingstructural formula

from Abbott Laboratories Inc., North Chicago, Ill., as disclosed in U.S.Pat. No. 5,767,144, the disclosure of which is incorporated herein byreference; matrix metalloproteinase inhibitors such as ABT-518{[S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoro-methoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide},having general formula C₂₁H₂₂F₃NO₈S and having the following structuralformula

from Abbott Laboratories Inc., North Chicago, Ill., which is disclosedin U.S. Pat. No. 6,235,786, the disclosure of which is incorporatedherein by reference; ABT 620{1-Methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide}, which isdisclosed in U.S. Pat. No. 6,521,658, the disclosure of which isincorporated herein by reference; antiallergic agents such aspermirolast potassium nitroprusside, phosphodiesterase inhibitors,prostaglandin inhibitors, suramin, serotonin blockers, steroids,thioprotease inhibitors, triazolopyrimidine, and nitric oxide.

While the foregoing beneficial agents are known for their preventive andtreatment properties, the substances or agents are provided by way ofexample and are not meant to be limiting. Further, other beneficialagents that are currently available or may be developed are equallyapplicable for use with the present invention.

If desired or necessary, the beneficial agent can include a binder tocarry, load, or allow sustained release of an agent, such as but notlimited to a suitable polymer or similar carrier. The term “polymer” isintended to include a product of a polymerization reaction inclusive ofhomopolymers, copolymers, terpolymers, etc., whether natural orsynthetic, including random, alternating, block, graft, branched,cross-linked, blends, compositions of blends and variations thereof. Thepolymer may be in true solution, saturated, or suspended as particles orsupersaturated in the beneficial agent. The polymer can bebiocompatible, or biodegradable.

For purpose of illustration and not limitation, the polymeric materialinclude phosphorylcholine linked macromolecules, such as a macromoleculecontaining pendant phosphorylcholine groups such aspoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate, polycaprolactone, poly-D,L-lactic acid, poly-L-lacticacid, poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly(aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen,cellulose, starch, collagen, PARYLENE®, PARYLAST®, polyurethaneincluding polycarbonate urethanes, polyethylene, polyethyleneterapthalate, ethylene vinyl acetate, ethylene vinyl alcohol, siliconeincluding polysiloxanes and substituted polysiloxanes, polyethyleneoxide, polybutylene terepthalate-co-PEG, PCL-co-PEG, PLA-co-PEG,polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinationsthereof. Non-limiting examples of other suitable polymers includethermoplastic elastomers in general, polyolefin clastomers, EPDM rubbersand polyamide elastomers, and biostable plastic material such as acrylicpolymers, and its derivatives, nylon, polyesters and epoxies.Preferably, the polymer contains pendant phosphoryl groups as disclosedin U.S. Pat. Nos. 5,705,583 and 6,090,901 to Bowers et al. and U.S. Pat.No. 6,083,257 to Taylor et al., which are all incorporated herein byreference.

The beneficial agent can include a solvent. The solvent can be anysingle solvent or a combination of solvents. For purpose of illustrationand not limitation, examples of suitable solvents include water,aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones,dimethyl sulfoxide, tetrahydrofuran, dihydrofuran, dimethylacetamide,acetates, and combinations thereof. Preferably, the solvent is ethanol.More preferably, the solvent is isobutanol. Additionally, in anotheraspect of the invention, multiple beneficial agents are dissolved ordispersed in the same solvent. For purpose of illustration and not forlimitation, dexamethasone, estradiol, and paclitaxel are dissolved inisobutanol. Alternatively, dexamethasone, estradiol, and paclitaxel aredissolved in ethanol. In yet another example, dexamethasone, estradiol,and ABT-578, i.e., the rapamycin analog,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,3H)-pentone,are dissolved together in one solvent. Preferably, the solvent isethanol. More preferably, the solvent is isobutanol.

Additionally, the beneficial agent includes any of the aforementioneddrugs, agents, polymers, and solvents either alone or in combination.

A number of methods can be used to load the beneficial agent onto thesurface of the prosthesis to provide for a controlled local arealdensity of beneficial agent if performed appropriately. For example, theprosthesis can be constructed to include pores or reservoirs which areimpregnated or filled with beneficial agent or multiple beneficialagents. The pores can be sized or spaced apart to correspond to or limitthe amount of beneficial agent contained therein in accordance with thedesired local areal density pattern along the length of theinterventional device, wherein larger pores or more dense spacing wouldbe provided in such portions intended to have a greater local arealdensity. Alternatively, uniform pores sizes can be provided but theamount of beneficial agent loaded therein is limited accordingly.Additionally, if desired, a membrane of biocompatible material can thenbe applied over the pores or reservoirs for sustained or controlledrelease of the beneficial agent from the pores or reservoirs.

According to some of the embodiments, the beneficial agent can be loadeddirectly onto the prosthesis or alternatively, the beneficial agent isloaded onto a base material layer that is applied to a surface of theprosthesis. For example and not limitation, a base coating, such as abinder or suitable polymer, is applied to a selected surface of theprosthesis such that a desired pattern is formed on the prosthesissurface. Beneficial agent is then applied directly to the pattern of thebase material.

In one aspect of the invention, the desired pattern corresponds to thedesired controlled local areal density. For example, a greater amount ofbase material layer is applied to portions of the interventional deviceintended to have a greater local areal density of beneficial agent, anda lesser amount of base material is applied to portions of theinterventional device intended to have a lower local areal density ofbeneficial agent.

Alternatively, a suitable base coating capable of retaining beneficialagent therein can be applied uniformly over the surface of theprosthesis, and then selected portions of the base coating can be loadedwith the beneficial agent in accordance with the invention. A greateramount of beneficial agent would be loaded over a unit surface area ofthe base coating intended to have a greater local areal density and alower amount of beneficial agent would be loaded over a unit surfacearea intended to have a lower local areal density.

In yet another embodiment of the present invention, the beneficial agentcan be applied directly to the surface of the prosthesis. Generally abinder or similar component can be required to ensure sufficientadhesion. For example, this coating technique can include admixing thebeneficial agent with a suitable binder or polymer to form a coatingmixture, which is then coated onto the surface of the prosthesis. Thecoating mixture is prepared in higher or lower concentrations ofbeneficial agent as desired, and then applied to selected portions ofthe prosthesis appropriately.

In any of the embodiments disclosed herein, a porous or biodegradablemembrane or layer made of biocompatible material can be coated over thebeneficial agent for sustained release thereof, if desired.

Conventional coating techniques can be utilized to coat the beneficialagent onto the surface of the prosthesis such as spraying, dipping orsputtering and still provide the desired effect if performedappropriately. With such techniques, it may be desirable or necessary touse known masking or extraction techniques to control the location andamount in which beneficial agent is loaded. Prior to coating theprosthesis with beneficial agent, optical machine vision inspection ofthe prosthesis preferably is utilized to ensure that no mechanicaldefects exist. Defective prostheses thus can be rejected before wastingbeneficial agent, some of which may be very costly.

In accordance with one aspect of the invention, however, the beneficialagent is “printed” onto the surface of the prosthesis by afluid-dispenser having a dispensing element capable of dispensingbeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. If desired, printing can be combined withconventional coating techniques such as spraying or dipping.

“Fluid-dispenser,” as used herein, refers broadly to any device having adispensing element capable of dispensing fluid in discrete dropletswherein each droplet has a controlled trajectory. For purposes ofillustration and not limitation, examples of such fluid-dispensersinclude fluid-jetting and similar fluid dispensing technology devicessuch as a drop-on-demand fluid printer and a charge-and-deflect fluidprinter. However, other fluid-dispensers capable of forming a fluid jetor capable of dispensing discrete droplets having a controlledtrajectory are within the scope of the present invention. In a preferredembodiment, the fluid-dispenser is a fluid-jet print head. Suchequipment is available from MicroFab Technologies of Plano, Tex.

Fluid-jetting and similar technology provides numerous advantages notavailable with conventional loading techniques. For example, fluidjetting technology can be used to deposit materials, such as chemicalreagents, in controlled volumes onto a substrate at a controlledlocation, as disclosed in U.S. Pat. No. 4,877,745 to Hayes et al.,incorporated herein by reference.

Fluid jetting can also be used to deposit materials in a reproducibleway. Fluid-jet based deposition of materials is data driven,non-contact, and requires no tooling. The “printing” information can becreated directly from CAD information and stored digitally in softwareor hardware. Thus, no masks or screens are required. As an additiveprocess with no chemical waste, fluid-jetting is environmentallyfriendly. Other advantages include the efficiency of fluid jet printingtechnology. For example, fluid-jetting can dispense spheres of fluidwith diameters of 15-200 um at rates of 1-25,000 per second for singledroplets on demand, and up to 1 MHz for continuous droplets. See Cooleyet al., “Applications of Ink-Jet Printing Technology to BioMEMS andMicrofluidic Systems,” Proc. SPIE Conf. on Microfluidics, (October2001), incorporated herein by reference.

In accordance with one aspect of the invention, a method of loadingbeneficial agent onto a prosthesis for delivery within a lumen isdisclosed. The method comprises the steps of providing a prosthesis,beneficial agent to be delivered from the prosthesis, and afluid-dispenser having a dispensing element capable of dispensing thebeneficial agent in discrete droplets, wherein each droplet has acontrolled trajectory. The method further includes creating relativemovement between the dispensing element and the prosthesis to define adispensing path and selectively dispensing the beneficial agent in araster format to a predetermined portion of the prosthesis along thedispensing path. In particular, the beneficial agent is selectivelydispensed from the dispensing element to a predetermined portion of theprosthesis in a raster format along a dispensing path. As used herein“raster format” refers to a continuous or non-continuous dispensingpattern of droplets of beneficial agent dispensed at specific intervals.The relative motion of the dispensing element and the prosthesis to beloaded with beneficial agent creates a dispensing path which includes,for example and as shown in FIG. 6 a, a sequential series of linearparallel passes 154 that traverse back and forth along one axis of theprosthesis. The relative motion is continued in a linear manner betweenforward and backward or right to left and left to right or upward anddownward, depending on the frame of reference. A traversal or a pass 154is completed when the relative motion reverses direction. That is,relative motion continues past the prosthesis, and then decelerates,stops, reverses direction and accelerates to a constant velocity. Aftereach pass, the position of the dispensing element 150 or prosthesis 10relative to the dispensing element preferably is changed or incrementedsuch that additional droplets do not impact in the same location duringthe subsequent pass, although a certain degree of overlap may bepermitted. For example, as the dispensing element dispenses thebeneficial agent along the prosthesis, a fluid dispensing width “w” isdefined. The dispensing path defined by the relative movement betweenthe dispensing element and the prosthesis can include a series ofparallel passes wherein each parallel pass has a path width no greaterthan the fluid dispensing width defined by the dispensing element,although a greater path width can be defined if desired.

Alternatively, the dispensing path created by the relative motion of thedispensing element 150 and the prosthesis 10 can include a singlecontinuous helix that wraps continuously around the prosthesis tubularbody and along the length of the prosthesis. FIG. 10 schematicallydepicts such a helical path. In this manner, selectively fluiddispensing in a raster format similar to that of the linear pathspreviously described can be performed using a helical path if desired.In a preferred embodiment, the direction of travel of relative motionconsists of continuously rotating, for example, the prosthesis 10 to beloaded and then incrementally advancing the dispensing element axiallyalong the prosthesis. Both axial and radial motion preferably beginbefore the prosthesis 10 is aligned with the dispensing element 150 toreceive droplets, so as to enable acceleration of both axes to aconstant velocity, and continues beyond the prosthesis where bothmovements may decelerate, and stop. After each rotation, the position ofthe dispensing element 150 or of the prosthesis 10 relative to thedispensing element is moved or incremented axially such that additionaldroplets of beneficial agent preferably do not impact in the samelocation, Any degree of overlap may be permitted to achieve the desiredareal density of beneficial agent.

For purpose of illustration of this method, and as shown in FIGS. 6 and7, the prosthesis 10 includes a plurality of interconnected structuralmembers 12 defining openings 14 therebetween and the beneficial agent 15is dispensed only when the dispensing element 150 and the structuralmembers 12 within a predetermined portion of the prosthesis 10 arealigned with each other. Accordingly, in this preferred embodiment,dispensing beneficial agent 15 ceases when the dispensing element 150and the structural members 12 of the prosthesis are not in alignment. Tothis end, the method can include a detecting step to determine when thedispensing element 150 is aligned with the structural members 12 of aprosthesis 10. The detecting step can be achieved by a sensor 160 suchas an optical detector, e.g., linear array detector or infrareddetector, ultrasound probe, temperature probe, camera, capacitancemeter, electrometer, hall-effect probe, and the like. However, anysensor 160 known in the art for detection is within the scope of theinvention. Alternatively, a controller 170 may be provided that isprogrammed with the structural member locations of a predeterminedportion of the prosthesis to be loaded with beneficial agent. In thismanner, the dispensing step is performed by the dispensing element asoperated by the programmed controller. These aspects of the inventionreduce or eliminate webbing and bridging of beneficial agent acrossopenings or gaps within the structure of the prosthesis and minimizeswaste. Furthermore, the dispensing element 150 can be aligned such thatthe controlled trajectory of each droplet is directed normal to thesurface of the prosthesis, or at an angle thereto. Similarly, thetrajectory path can be aligned to cross the central axis of theprosthesis, or be aligned off-axis thereto.

According to another aspect of the invention, the method of loadingbeneficial agent onto the prosthesis includes providing a prosthesisincluding a tubular member having a central axis defined along a lengthof the tubular member. This method further includes dispensingbeneficial agent from a dispensing element capable of dispensingbeneficial agent in discrete droplets and in a controlled trajectory toa surface of the prosthesis, wherein the controlled trajectory ofbeneficial agent is aligned so as not to intersect the central axis ofthe tubular member.

For example, and for purpose of illustration and not limitation, FIGS. 8a-8 d depict various cross-sections of the interventional device 10 ofFIG. 6. In each cross-sectional view, the trajectory path 152 of thediscrete droplets 155 is aligned “off-axis” so as not to pass throughthe central axis 11 of the tubular member. Particularly, and as depictedin FIGS. 8 a through 8 d for purpose of illustration and not limitation,the trajectory path 152 of the discrete droplets 155 is alignedtangentially between an inner surface and an outer surface of thetubular wall of the prosthesis 10. In this manner, likelihood of impactof a discrete droplet 155 of beneficial agent 15 with a surface of theprosthesis 11 is enhanced. If desired, however, alternative off-axistrajectory path alignment can be used in accordance with the invention.

With reference to FIGS. 8 a-8 d, the prosthesis provided by theprosthesis providing step includes a tubular member having a pluralityof interconnected structural members 12 defining openings 14therebetween, and further wherein the controlled trajectory 152 of eachdroplet is substantially tangential to a wall or surface of thestructural members 12 within the predetermined portion of theprosthesis. In this regard, the controlled trajectory 152 of beneficialagent 15 dispensed from the dispensing element 150 is aligned such thatit does not intersect the central axis of the prosthesis. This processallows for greater coverage of the structural elements, withoutrequiring selective operation of the dispensing element, if desired.That is, use of the “off-axis” approach allows for enhanced loading ofbeneficial agent on the prosthesis without selective or with onlylimited control of the dispensing element if desired. In a preferredembodiment, however, the dispensing element is at least controlled toterminate dispensing when the trajectory path is not aligned with thesolid profile of the predetermined area to be loaded, e.g. axiallybeyond either end 13 of the prosthesis 10, shown in FIG. 6. Inparticular, the dispensing element is turned “on” only when thetrajectory path of beneficial agent will intersect the solid area sweptout by 360 degrees rotation of the prosthesis. The dispensing element isturned off when the trajectory path of beneficial agent would notintersect or will miss the solid area and volume swept out by 360degrees rotation of the prosthesis.

Alternatively, and in accordance with a preferred embodiment of theinvention, the “off-axis” method is performed using the raster techniquepreviously described. That is, with the trajectory path 152 alignedoff-axis from the central axis of the prosthesis 10, such as shown inFIGS. 8 a-8 d, discrete droplets can be selectively dispensed from thedispensing element 150 only when aligned with a structural member 12 ofthe prosthesis 10. In this embodiment, the relative motion of thedispensing element 150 and the prosthesis 10 define a dispensing pathwhich includes a sequential series of linear parallel passes thattraverse back and forth along one axis of the prosthesis. The relativemotion alternates between forward and backward, right to left, left toright, or upward and downward, depending on the frame of reference. Atraversal or pass is completed when the relative motion changesdirection. That is, relative motion continues past the prosthesis andthen decelerates, stops, reversed direction and accelerates to aconstant velocity. After each pass, the position of the dispensingelement 150 is changed or incremented such that additional drops ofbeneficial agent do not impact the same location as the previouslydispensed droplets during the subsequent pass. Any degree of overlap maybe permitted to achieve a desired areal density of beneficial agent.

Alternatively, the relative motion of the dispensing element and theprosthesis define a dispensing path which includes a single continuoushelix that wraps around the prosthesis and along its length. Therelative motion consists of continuously rotating, for example, theprosthesis and then incrementally advancing the dispensing element 150axially along the prosthesis. Both axial and radial motion preferablybegin before the item is aligned with the dispensing element to receivedroplets of beneficial agent, so as to enable acceleration of both axesto a constant velocity, and continues beyond the prosthesis where bothmovements may decelerate, and stop. After each rotation, the position ofthe dispensing element or prosthesis relative to the dispensing elementis moved or incremented axially such that additional droplets preferablydo not impact in the same location. However, any degree of overlap maybe permitted to achieve a desired areal density of beneficial agent.

The linear velocity during dispensing of droplets of beneficial agentcan be constant or can be varied in a controlled way. Further, thepreferable position of the droplet trajectory is such that the dropletsinteract with the structural surfaces of the prosthesis at or near thetangent to its curved solid surface.

In a preferred embodiment the dispensing path 154 includes a series ofparallel passes along a surface of the prosthesis. For example and notlimitation, the prosthesis provided can have a tubular body prior to itsdeployment in a lumen, and each parallel pass of the dispensing path 154is parallel to the longitudinal axis 11 of the prosthesis 10 as shown inFIG. 6 a. After each pass, the position of the dispensing element 150 orprosthesis 10 is changed or incremented so that the discrete droplets155 of beneficial agent 15 are dispensed onto a surface of theprosthesis 10 that has not already been loaded. Alternatively, and aspreviously noted, the parallel passes can define a helical patternaround the longitudinal axis of the stent, wherein each pass is acomplete turn of the helical pattern. For purposes of illustration andnot limitation, the relative motion of the dispensing element and theprosthesis can include continuously rotating the prosthesis andincrementally advancing the dispensing element axially along the lengthof the prosthesis. Preferably, after each rotation of the prosthesis,the position of the dispensing element is incrementally changed axiallysuch that additional droplets of beneficial agent that are dispensedfrom the dispensing element load a surface of the prosthesis not alreadyloaded by a prior pass. In an alternative aspect of the invention, theprosthesis can have a planar body prior loading, such that no rotationof the planar member is required for loading of beneficial agentthereon. The step of dispensing the beneficial agent onto the prosthesisalong the dispensing path can be repeated to provide multiple passesalong a predetermined portion of the prosthesis.

As noted above, the beneficial agent is selectively dispensed from thedispensing element along the dispensing path in a raster format. In thismanner, the raster format can be achieved by turning the dispensingelement on and off at predetermined intervals in response to a detector.Alternatively, the beneficial agent can be selectively dispensed in araster format by programming a controller device that communicates withthe dispensing element to dispense the beneficial agent according to theprogrammed data. A variety of fluid dispensers are available andsuitable for providing discrete droplets along a controlled trajectory.For example, a suitable drop-on-demand jetting system can be used, asshown in FIGS. 9 and 11, wherein discrete droplets are selectivelydispensed from a jetting head. In this manner, the jet stream ofdiscrete droplets can be turned on and off on demand, and the flow rateof discrete droplets can be increased or decreased as desired.Alternatively, if a charge-and-deflect device is used, then a continuousstream of droplets will be generated, and selected droplets will bedeflected as is known in the art, such as shown in FIG. 7, as describedfurther below.

In an embodiment of the invention the prosthesis is a stent, and asmentioned above, the fluid-dispenser is a fluid-jetting device. Inaccordance with the preferred embodiment, a driver 120 continuallyadvances the stent longitudinally along its axis at a constant rate, todefine a series of generally parallel passes 154 along the longitudinalaxis 11 of the stent 10. The stent is the incrementally rotated aboutits axis at the end of each pass. The stent is rotated at about 1 degreeto about 20 degrees about its longitudinal axis, increments, andpreferably is rotated at about 5 degree increments.

The fluid-jetting head is turned on to provide droplets of beneficialagent whenever a stent strut or structural member is detectedimmediately in front of the jetting head, or based on a predeterminedprogrammed pattern that corresponds to the stent design, as mentionedabove. By further providing controlled flow rate dispensed from thejetting head, the beneficial agent can be provided in a rastered formatto confer the stent with a known quantity of beneficial agent. Ifdesired, the known quantity of beneficial agent is dispensed to providea uniform local areal density based on changes in surface area. As usedherein “local areal density” refers to the amount of beneficial agentper unit surface area of the stent or prosthesis.

For example and not limitation, a unit length of two different strutshaving different strut widths could each be loaded with an equal amountof beneficial agent by adjusting flow rate accordingly. Contrastly, theflow rate of the jetting head can be controlled along the progression ofthe stent to provide a first portion 10 b of the prosthesis 10 with agreater local areal density and a second portion 10 a of the prosthesiswith a lower local areal density, such as shown in FIG. 1. Similarly,the rate of relative movement between the jetting head and theprosthesis can be varied to control local areal density accordingly.

As noted above, the dispensing path 154 is defined by the relativemovement between the dispensing element and the prosthesis. The relativemovement between the dispensing element and the prosthesis may beperformed at a substantially constant velocity, or alternatively at avaried velocity to alter local areal density of beneficial agent, orintermittently. For an example of varied velocity, and with reference tothe embodiment of FIG. 1 a for purpose of illustration and notlimitation, the linear travel speed of the prosthesis under the fluiddispenser is performed 50% faster during loading of beneficial agent onthe proximal and distal portions 10 a and 10 c of the prosthesis body todecrease local areal density accordingly. Alternatively, the lineartravel speed of the prosthesis under the fluid dispenser may be 50%slower during loading of beneficial agent on the mid region of theprosthesis body to increase local areal density thereat.

Alternatively, rather than using a raster format, a vector technique canbe used wherein a first portion of the stent strut at one end of thestent is positioned in front of the jetting head and the jetting head isturned on. The jetting head is then left on to dispense droplets ofbeneficial agent at a constant predetermined frequency to provide apredetermined dispensing rate of agent. The two-axis control system,described further below, is directed to continuously move the stent,coordinating both axes simultaneously so that the predetermined shape ofthe stent struts are advanced in front of the jetting head. Thismovement continuously places the beneficial agent on the struts of thefirst portion until the desired surface of the stent has been positionedto receive beneficial agent over the known surface area, and apredetermined quantity of beneficial agent has been dispensed. Thebeneficial agent is provided on the stent struts and the jetting headthereby does not disperse beneficial agent in areas wherein metal hasbeen removed from the stent. This process may be repeated for subsequentportions of the interventional device, such that known quantities ofbeneficial agent are provided over each corresponding portion of theinterventional device. As with the raster format, flow rate or rate ofrelative movement can be controlled to adjust local areal density ofbeneficial agent as desired.

In yet another embodiment, the two-axis positioning system is coupled toa charge-and-deflect jetting head. A charge-and-deflect jetting head iscapable of producing a rastered pattern of droplets over a predeterminedwidth of the stent. That is, it is also in accordance with the inventionto apply a surface charge to selected droplets of beneficial agentdispensed from the dispensing element. Preferably, if a positive surfacecharge is applied to the beneficial agent, an antioxidant can beincluded in the beneficial agent. In this manner, the antioxidant canhelp to prevent the oxidation of a beneficial agent that might otherwiseoxidize when positively charged. Additionally, or alternatively, otherknown techniques can be used to prevent or inhibit oxidation ofbeneficial agent. The trajectory of charged droplets of beneficial agentcan be altered by a deflection field. For example, an electrode 144 maybe used to deflect the trajectory of beneficial agent, which is chargedby a charger 142, towards a predetermined portion of the prosthesis asshown in FIG. 7. If desired, a charge opposite that induced on thedroplets of beneficial agent can be applied to a predetermined portionof the prosthesis to provide an electrostatic attraction between thedroplets of beneficial agent and the prosthesis for greater accuracy andefficiency.

To effect predetermined loading of beneficial agent, or coatingthickness, several methods of controlling the two-axis positioningsystem in coordination with control of the fluid dispensing are possibleso as to result in a precise deposition of beneficial agent on the outersurface of the stent or prosthesis 10. First, the motor 122 thatcontrols rotation of the prosthesis about its longitudinal axis can beturned on to produce a constant angular velocity. A second motor 124 isthen controlled to advance the prosthesis or stent in front of thedispensing element 150 at a predetermined rate to generally describe aspiral or helix across the longitudinal axis of the stent, where thepitch width, from rotation to rotation, is the same as the raster widthof the dispensing element 150. When a charge-and-deflect dispensingelement is used, the surface of the prosthesis 10 or stent can beexposed to the dispensing element 150 in a more rapid manner than forthe single drop wide raster pattern that is possible with thedrop-on-demand mode system. When the first stent strut is detected to bepresent in front of the jet head 150, a bit-mapped pattern that has beenpreviously stored in memory 170 to describe the shape of the struts israstered out by providing appropriate charges on selected droplets.Second, a linear array detector 160 with resolution similar to thenumber of droplets in each raster line can detect, by reflected ortransmitted light, the presence of a stent strut that is about torevolve in front of the jetted fluid window. The data from this type ofdetector can then be transferred to a shift register which produces thenecessary raster data by shifting the bit pattern out a bit at a time.With this method, no predetermined bit-map is necessary, and any slightvariations in speed, edge detection or position may be automaticallycompensated. This process may be repeated for subsequent portions of theinterventional device, such that known quantities of beneficial agentare provided over each corresponding portion of the interventionaldevice.

Further in accordance with the invention, a system for loadingbeneficial agent onto a prosthesis for delivery within a lumen isprovided. As shown in FIGS. 7 and 13, the system includes a holder 110for supporting a prosthesis and a fluid-dispenser having a dispensingelement 150 capable of dispensing beneficial agent 15 in discretedroplets 155, each droplet having a controlled trajectory.

The holder includes a mandrel or spindle 112 made of any suitablematerial known in the art. Preferably, however, the spindle 112comprises a superelastic material, such as nitinol, or any othermaterial that has shape memory properties. Particularly, manipulation ofa stent holder made of stainless steel can result in bending anddeformation of the spindle. Such deformation causes poor rotationalaccuracy and high run-out, e.g., 0.25-2.5 mm, from one end of thespindle to the other end of the spindle. This can cause a lowerefficiency of loading beneficial agent onto a prosthesis, and lowerefficiency of droplet interaction with the prosthesis because theposition of the stent under the jetting head varies as the run outvaries. Superelastic materials generally have properties that are ableto absorb and recover from up to 8% strain force. Thus, advantageously,nitinol provides a more resilient spindle capable of undergoing repeatedmanual stent mounting without the plastic deformation that occurs with astainless steel spindle design.

For purpose of illustration and not limitation, and as shown in FIG. 13,a nitinol spindle 112 may be made using a centerless grinding techniqueto obtain high concentric accuracy. Despite this grinding process, thecenterline of the small diameter part of the spindle (e.g., 0.5 mmdiameter) can vary a few degrees from the centerline of the intermediatediameter section (e.g., 2 mm diameter). This variance can be removed byheating the spindle near the junction of the small and intermediatediameter section and bending it to remove most of the residual run out.Upon cooling, the spindle, shown in FIG. 13, assembly retains its newposition. The final run out on an exemplary spindle after using thesetechniques was about 0.051 mm.

The system also includes a driver such as a driver assembly 120 tocreate relative movement between the holder 110 and the dispensingelement 150, and a controller 170 in communication with the driver 120to define a dispensing path of relative movement between the dispensingelement 150 and the holder 110. The controller also communicates withthe dispensing element 50 for selectively dispensing beneficial agent ina selected format along the dispensing path onto a selected portion ofthe prosthesis 10 supported by the holder 10. In one aspect of theinvention the holder 110 supporting the prosthesis 10 is moveable whilethe dispensing element 150 remains stationary during dispensing ofbeneficial agent 15. However, in another aspect of the invention theholder 110 supporting the prosthesis 10 remains stationary while thedispensing element 150 moves along the dispensing path.

Alternatively, both the holder 110 and dispensing element 150 aremoveable. In another aspect of the embodiment, as previously described,the system includes a detector 160 to detect when the dispensing element150 is aligned with the predetermined portion of the prosthesis 10.Various known components can be used in combination for construction ofthe system of the present invention. For example, jetLab System II fromMicroFab Technologies of Plano, Tex., as modified to include the desiredfeatures of the invention can be used.

In yet another embodiment of the invention, a determination of thequantity of beneficial agent dispensed over a given or known surfacearea can be established. According to one aspect, a predetermined ratioof an identifiable marker is added to the beneficial agent and both thebeneficial agent and the marker are loaded onto the prosthesis.Subsequently, the amount of identifiable marker loaded onto theprosthesis is detected to determine the amount of correspondingbeneficial agent loaded onto the prosthesis. In one aspect of theinvention, the identifiable marker includes radiopaque material. Afterloading the radiopaque material with the beneficial agent onto theprosthesis, the prosthesis is imaged and an intensity value is measuredto determine the amount of beneficial agent loaded thereon and thuslocal areal density. The identifiable marker in this aspect can alsoinclude a fluorescent dye, e.g., coumarin dye. In another aspect of theinvention, the identifiable marker includes charged particles, forexample and not limitation, protons or electrons. After loading themarker and beneficial agent onto the prosthesis the detecting stepincludes measuring a charge build-up on or current flow from theprosthesis resulting from the charged particles. The charge build-up orcurrent flow therefore generally corresponds to the amount of beneficialagent loaded onto the prosthesis. Alternatively, because the fluidjetting technology of the present invention is inherently digital, thequantity of beneficial agent dispensed can be determined by counting thedroplets that have been jetted or dispersed.

In yet another alternative, the amount of beneficial agent loaded can bemeasured more generally by weighing the stent before the jettingoperation and then after the jetting operation. The weight differencecorresponds to the drug loaded with the concentration being a functionof the jet flow rate along the length of the stent. Yet another methodis to integrate the charge build-up on the prosthesis when acharge-and-deflect system is used. Since each droplet in acharge-and-deflect jetting system has had a surface charge injected ontoit to enable the droplet to be deflected in an electrostatic field,either the loss of charge at the charging electrode or the accumulationof charge on the prosthesis can be integrated over time to determine thetotal volume of fluid that has accumulated on the surface of the device.

Also in accordance with the invention, an on-board spectrometer may beutilized for monitoring the beneficial agent concentration on the jetterreservoirs as a function of time. It is desirable to load beneficialagent such as a drug at a constant concentration. However, due to theevaporation of solvent during the loading process, the concentration ofdrug will increase. Advantageously, a spectrometer can be configuredwith a pump to add solvent to the drug such that a constant absorbanceon the spectrometer is maintained. The constant absorbance level of thespectrometer is pre-set to monitor an appropriate wavelength. Themaintenance of a constant absorbance reading on the spectrometer by theaddition of solvent translates to the maintenance of a pre-set drugconcentration.

For drop-on-demand jetting systems, this same drug quantificationconcept can be utilized by adding a constant voltage charging electrodeadjacent to the nozzle of the dispenser so as to add a polar charge toeach droplet. The coating on the stent, if an insulator, will act as acapacitor to the charge. This detection technique will be able to detectcharge build up if a small leakage path is provided or if a secondreference surface is provided against which to compare charge build up.Other alternative techniques can be used. For example, if a metalmandrel is present inside the stent it may be used to monitor any lostdroplet or splash. The charge that directly transfers to this“electrode” will create an opposite polarity current to the chargepresented to the insulated coated surface of the stent.

For each of these detection techniques described above, an appropriatedetector can be incorporated in the system of FIG. 7, preferably incommunication with controller 170.

In accordance with another aspect of the invention, a second beneficialagent or multiple beneficial agents can be loaded onto the prosthesis asdescribed above. Therefore, further in accordance with the invention, aninterventional device comprising a prosthesis loaded with a plurality ofdiscrete droplets of a first beneficial agent and a plurality ofdiscrete droplets of a second beneficial agent is provided, such as byusing the system and method shown in FIG. 9.

Particularly, the method described in detail above for one beneficialagent can be modified to allow for loading multiple beneficial agentsonto a prosthesis, which might ordinarily lead to undesirable resultswhen using conventional loading techniques. For example and notlimitation, the first beneficial agent and the second beneficial agentmay have different physical and/or chemical characteristics preventingthe beneficial agents from being capable of dissolving in the samesolvent, or at the same pH or temperature. In particular, the firstbeneficial agent can be dissolved in a solvent that is immiscible withthe solvent in which the second beneficial agent is dissolved.Alternatively, the first beneficial agent and the second beneficialagent may be incompatible with each other. In particular, the firstbeneficial agent and the second beneficial agent can be undesirablychemically reactive or may have undesirably different release rates (orcontrarily, undesirably similar release rates). Additionally, the firstand second beneficial agents can simply be detrimental to each other,e.g., one of the beneficial agents may degrade the efficacy of the otherbeneficial agent. Thus, although loading the particular multiplebeneficial agents onto the same surface of a prosthesis can be desiredit often may be problematic due to some incompatibility when using aconventional loading technique. In accordance with the presentinvention, a method of loading such beneficial agents and aninterventional device for the delivery of such beneficial agents isprovided.

As noted above, the beneficial agents are loaded in a plurality ofdiscrete droplets on the surface of the prosthesis. The discretedroplets of multiple beneficial agents are preferably loaded onto theprosthesis as unmixed droplets to provide an interspersed pattern oralternatively, the unmixed droplets of beneficial agent can be loadedonto the prosthesis to provide an overlapping pattern of the firstbeneficial agent and the second beneficial agent. In this manner, theedges of the droplets overlap or alternatively, a larger surface of thedroplet overlaps other droplets to provide a layering effect, asdepicted in FIG. 10.

Multiple fluid-dispensers are in accordance with the invention, whereineach beneficial agent to be loaded onto the prosthesis is dispensed froma distinct dispensing device. For purpose of illustration and notlimitation as shown in FIG. 9, a first dispenser 150 is provided with afirst beneficial agent 15′ dissolved in a solvent that is compatible forthat particular first beneficial agent. Further, a secondfluid-dispenser 150″ is provided with a second beneficial agent 15″ thatis different from the first beneficial agent 15′, and requiring adifferent solvent for compatibility. For example, the first beneficialagent could be a water-soluble agent, whereas the second beneficialagent could be a water-insoluble agent, each requiring a differentsolvent. Accordingly, both beneficial agents are loaded onto the samesurface of the prosthesis without problems arising from theirimmiscibility.

Where two fluid-dispensers are used to load the multiple beneficialagents onto the prosthesis, the trajectories of discrete dropletscorresponding to each of the first beneficial agent and the secondbeneficial agent can be aligned such that the droplets from eachbeneficial agent combine and mix prior to their being loaded on theprosthesis. In this manner, the first and second beneficial agent canform a third beneficial agent which is loaded onto the prosthesis. Forpurpose of illustration and not limitation, the first beneficial agentmay be bisphenol-A-diglycidyl ether and the second beneficial agent canbe triethylenetetramine. Upon combination of the first beneficial agentand the second beneficial agent, a cross linked coating is formed toprovide a third beneficial agent. In yet another illustrative example,the first beneficial agent can be bisphenol-A-diglycidyl ether andpaclitaxel and the second beneficial agent can be triethylenetetramine.Upon the combination of the two controlled trajectories of beneficialagents, a third beneficial agent is formed, a cross-linked coatingentrapping paclitaxel, which is loaded on the prosthesis. Alternatively,the discrete droplets of the first and second beneficial agent can bealigned along trajectories to mix on the surface of the prosthesis.

As noted above, the beneficial agent can include a drug and polymermixture. In accordance with the method of the invention, the first andsecond beneficial agents can correspond to drug-polymer mixtures havingdifferent concentrations of polymer to effect different release rates ofthe particular drug in each beneficial agent. For example, thedrug-polymer mixture having a higher concentration of polymer would havea slower release of the drug within the lumen than a drug-polymermixture having a lower concentration. Alternatively, rather thanproviding drug-polymer mixtures having different polymer concentrationsto provide different release rates, it is also possible to dispensebeneficial agents using different polymers or other binders, wherein thespecific polymer or binder has different diffusivity or affinity toassure delivery of the beneficial agents at different rates. Thus, inaccordance with the invention, multiple beneficial agents can bereleased at rates appropriate for their activities, such that theprosthesis of the invention has multiple beneficial agents which eluteoff the prosthesis at desired rates.

For example, a cationic phosphorylcholine-linked polymer which has ahigher affinity for anionic therapeutic agents can be blended anddispersed as a first beneficial agent and lipophilicphosphorylcholine-linked polymer can be blended with lipophilic drugs asthe second beneficial agent to effect different release ratesrespectively.

In yet another embodiment of the invention, one of the first and secondbeneficial agents loaded onto the prosthesis can be more hydrophobic orless water-soluble than the other. Thus, in accordance with theinvention is provided a prosthesis including first and second beneficialagents wherein one of the beneficial agents is more hydrophobic or lesswater soluble than the other. In this manner, the more hydrophobicbeneficial agent acts as a water barrier or hydration inhibitor for theless hydrophobic beneficial agent, thereby reducing the release rate ofthe less hydrophobic beneficial agent as disclosed in U.S. ProvisionalPatent Application 60/453,555 and PCT/US03/07383, each of which wasfiled on Mar. 10, 2003, and each of which is incorporated herein byreference thereto.

In addition to providing a prosthesis having multiple beneficial agentswhich are delivered at unique or desired rates, according to anotheraspect of the invention, the first beneficial agent can be dissolved insolvent wherein the second beneficial agent causes the first beneficialagent to precipitate out of the solvent. For example and not limitation,the first beneficial agent may be rapamycin dissolved in ethanol, andthe second beneficial agent may be water. Upon droplet combination usingthe method and system of the invention, the rapamycin will precipitatewithin the droplet and be deposited on the prosthesis as amicroprecipitate.

In yet another aspect of the invention, at least one of the first andsecond beneficial agents can be mixed with a binder prior to beingloaded onto the prosthesis. Further in accordance with this aspect oneof the beneficial agents can be a curative agent for curing the binderon the prosthesis with the beneficial agent mixed therein. For example,see Example 4 below.

As noted above, one of the beneficial agents can be a solvent for theother beneficial agent. Thus, in accordance with the invention, thefirst beneficial agent, e.g., a drug, polymer, or a combination thereof,can be loaded onto the prosthesis, and subsequently the secondbeneficial agent, i.e., a solvent, can be loaded onto the prosthesis soas to redistribute the first beneficial agent more uniformly along theprosthesis.

As also noted above, the prosthesis can include at least one reservoiror cavity or trough therein. For purpose of illustration and notlimitation, computer controlled profiles of a laser cut stent can beutilized to precisely deposit beneficial agent into the laser cuts onthe stent struts. For example, a longitudinal trough can be laser cut,etched, or otherwise formed into the strut, such as in the curve or bendof the strut for instance. In accordance with a preferred aspect of theinvention, the cavity or trough is provided with a contouredcross-sectional profile for retention and elution of beneficial agenttherein. Particularly, and as depicted schematically in FIG. 12, thecross-sectional profile of the cavity or trough 16 includes a smallerdimension at the interface with the strut surface, so as to define amouth 17 of the trough 16, and a larger internal cross-dimension of thetrough to define a reservoir 18. FIG. 12 shows one such embodiment,wherein mouth 17 is defined for reservoir 18 of trough 16. Use of thefluid jet system and method of the present invention thus allows forbeneficial agent to be loaded into the mouth 17 of trough 16, withoutthe entrapment of air within the reservoir 18. An appropriate volume ofbeneficial agent is deposited in the laser cut profile to at leastpartially fill the reservoir 18. In this respect, beneficial agent thatis deposited in the longitudinal trough can include a combination ofdrugs or a combination of polymers or a combination of drugs andpolymers in different layers. Furthermore, different layers of polymerand/or drug having different concentrations, or different drug elutionrates can be loaded therein. Additionally, an interim polymer and/orfinal polymer overcoat can be applied over the beneficial agent. Such adeposition configuration in combination with cavities is particularlybeneficial for minimizing delamination of the polymer-drug layers, andalso provides versatility in controlling drug elution and the generationof various combinations of drug release patterns. A computer profilingapproach is also useful to coat drug and polymer layers on the distaland proximal edges of the stent.

In accordance with another aspect of the invention, one or more of thereservoirs or cavities or troughs is loaded with a more hydrophilicfirst beneficial agent and then a second more hydrophobic beneficialagent is loaded onto the first beneficial agent within the cavity orreservoir in a manner as described above.

Further in accordance with the invention, using the method and systemsdescribed above, a first beneficial agent loaded onto the prosthesis canhave a first local areal density and a second beneficial agent loadedonto the prosthesis can have a second local areal density. As usedherein, “areal density” refers to the amount of beneficial agent perunit surface area of a selected portion of the prosthesis. “Local arealdensity” refers to the dosage of beneficial agent per local surface areaof the prosthesis The local areal density of the first beneficial agentand the local areal density of the second beneficial agent can beuniform across each respective portion to define stepped changes inlocal area density as depicted in FIG. 1 b or can be varied across aselected portion of the prosthesis to define gradients of local areadensity, as depicted in FIG. 1 c. Accordingly, an interventional deviceis provided having a prosthesis that is at least partially loaded withbeneficial agent having a local areal density that is varied along aselected portion of the body of the prosthesis.

In accordance with a preferred embodiment, the prosthesis has a tubularbody when deployed in a lumen. Preferably, the tubular body includes afirst and second portion at least partially loaded with beneficial agentsuch that the first portion has a first local areal density and thesecond portion has a second local areal density. Each portion may bedefined as a preselected length of the prosthesis. Alternatively, asshown in FIG. 1 b, the first portion can be defined by a selected set ofinterconnected structural members and the second portion can be definedas a second set of interconnected members e.g., connectors elements orring-elements. For example and not limitation, at least one of the firstand second set of selected interconnected elements can define at leastone ring-shaped element extending around the circumference of theprosthesis.

In another embodiment of the invention, the local areal density isvaried as a continuous gradient along a selected portion of theprosthesis as shown in FIG. 1 c. Accordingly, in one aspect of theinvention the local areal density of beneficial agent is varied such asto provide a prosthesis having a local areal density of beneficial agentat the ends of the prosthesis that is different than the local arealdensity of beneficial agent at an intermediate section of theprosthesis. For purpose of illustration and not limitation, the localareal density of beneficial agent at the intermediate section of theprosthesis can be greater than that at the proximal and distal ends ofthe prosthesis as shown in FIG. 1 c. Alternatively, the proximal anddistal ends of the prosthesis can have a greater local areal density ofbeneficial agent than that on the intermediate section of theprosthesis. In a preferred embodiment of the invention, the varied localareal density of beneficial agent corresponds to the location of alesion when the prosthesis is deployed within a lumen. For example, theprosthesis can be loaded to have a greater local areal density ofbeneficial agent along a preselected portion of the prosthesis thatcorresponds to the location of the lesion when the prosthesis isdeployed in a lumen. Thus, targeted therapy may be achieved with theinterventional device of the present invention.

In accordance with the invention, the local areal density can be variedby varying the relative rate in which beneficial agent is loaded to aselected location along the prosthesis. To this end, the frequency inwhich the droplets of beneficial agent are applied along a unit lengthof the dispensing path to the prosthesis is varied. Alternatively, therelative rate of loading beneficial agent can be varied by varying therelative movement between the dispensing element and the prosthesis.Another alternative for varying the relative rate of loading beneficialagent is to vary the amount of beneficial agent per droplet dispensedfrom the dispensing element. Other alternatives for varying the localareal density of beneficial agent loaded onto the prosthesis includemixing the beneficial agent with a binder and varying the ratio ofbeneficial agent to binder. Alternatively, the amount of the mixture ofbeneficial agent and binder that is applied to the prosthesis can bevaried to achieve a varied local areal density of beneficial agent.Other methods of varying the local areal density of beneficial agentknown in the art may be used.

As noted above, the beneficial agent is at least partially loaded onto asurface of the prosthesis. Further in accordance with the invention theprosthesis includes a first surface and a second surface that are atleast partially loaded with beneficial agent. In one embodiment of theinvention, the first surface and the second surface each correspond toone of the inner surface and the outer surface of the prosthesis. Thus,according to this particular embodiment, beneficial agent, as definedabove, is loaded onto the inner or luminal surface of a prosthesis aswell as the outer surface of the prosthesis. The method described abovecan be used for this aspect of the invention, wherein the beneficialagent is loaded on the inner surface of the prosthesis by inserting afluid dispensing element within the inner diameter of the prosthesis, orby dispensing beneficial agent 15 diametrically across the prosthesis 10between structural members 12 to impact the inner surface on theopposite side of the prosthesis 10 as shown in FIG. 11. In this regard,the dispensing element 150″ is aligned so that the controlled trajectory152″ of discrete droplets 155″ of beneficial agent optimally intersectwith the inner surfaces of the structural features of the prosthesis 10and not intersect with the structural features of the outer surface ofthe prosthesis. For purposes of illustration and not limitation, for aprosthesis comprising an odd number of radial repeats in the pattern ofstructural features, the preferred alignment of the dispensing elementis orthogonal to the central axis of the prosthesis and in a plane thatintersects the central axis of the prosthesis. However, for a prosthesiscomprising an even number of radial repeats in the pattern of structuralfeatures, the preferred alignment of the dispensing element to theprosthesis is orthogonal to the central axis of the prosthesis, but in aplane that does not intersect the central axis of the prosthesis. Asanother example, for a prosthesis including a tubular member comprisingmultiple radially and axially repeating structural elements, thepreferred alignment of the dispensing element can be determined byassessing the shadow cast by the foreground or outer structural elementson the background or inner structural elements. The preferred plane toalign the dispensing element can be determined by assessing the plane inwhich the maximum amount of unobstructed inner surface is presented uponrotation of the tubular member.

In accordance with this aspect of the invention, the relative motion ofthe dispensing element and the prosthesis can be coordinated to enable apreprogrammed “raster” image of the position or locations of thestructural elements of the inner surface. Alternatively, the vectorpattern of the structural elements may be preprogrammed, as previouslydescribed. Also, in accordance with the invention, the beneficial agentis dispensed from the dispensing element along a controlled trajectorythat is substantially tangential to or near the outer surface of theprosthesis and is loaded on the inner surface of the structural elementsof the prosthesis.

In this aspect of the invention, the interventional device can bedesigned to provide combination therapy of beneficial agents to targetedlocations. For example and not limitation, the particular beneficialagent loaded to the luminal or inner surface of the prosthesis can beintended for systemic release, whereas the particular beneficial agentloaded onto the outer surface of the prosthesis is intended for releaseinto the wall of the lumen. In accordance with one aspect of theinvention, the beneficial agents loaded onto the luminal side or innersurface of the prosthesis include, without limitation, antiplateletagents, aspirin, cell adhesion promoters, agents that promoteendothelial recovery, agents that promote migration, and estradiol. Thebeneficial agents loaded onto the outer surface of the prosthesisinclude without limitation, anti-inflammatories, anti-proliferatives,smooth muscle inhibitors, cell adhesion promoters, and the rapamycinanalog ABT-578, i.e.,3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-3-methoxy-4-tetrazol-1-yl)cyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone;23,27-Epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,3H)-pentone

In accordance with another embodiment of the invention, the firstsurface of the prosthesis is defined by a plurality of interconnectingstructural members. Accordingly, the first surface can include a firstselected set of structural members, e.g., a connector member, and thesecond surface can include a second selected set of the structuralmembers, e.g., a ring-shaped element extending around the circumferenceof the prosthesis.

As noted above, the beneficial agent is loaded onto the prosthesis toprovide a controlled local areal density across a length of theinterventional device. That is, it may be desirable to provide a greaterconcentration of beneficial agent at one portion of a prosthesis and alower concentration, or perhaps no beneficial agent, at another portionof the prosthesis. For example, in one embodiment, a greater local arealdensity can be provided at a first portion, e.g., intermediate portion10 b, of a stent 10, as shown in FIG. 1 a, while providing a lower localareal density of beneficial agent to a second portion, e.g., one or bothend portions (10 a, 10 c), of the stent 10. In accordance with thepresent invention, each of the first and second portions of theprosthesis may be defined by any of a variety of patterns or selectedportions of the prosthesis. For example, the first portion of theprosthesis can be defined by longitudinal connectors whereas the secondportion of the stent is defined by annular rings, or vice versa, asillustrated in FIG. 6.

In accordance with another aspect of the present invention, theinterventional device includes a first prosthesis and a secondprosthesis in combination to define an overlapping portion and at leastone non-overlapping portion. For example, and as embodied herein, FIG. 2or 3 present a schematic representation of a nested interventionaldevice including a first prosthesis 20 and a second prosthesis 30configured to be deployed in an overlapping relationship. Theinterventional device, however, can optionally include more than twoprostheses in combination, if desired. Such interventional devices 50include but are not limited to nested stents and modular bifurcatedstents. For purpose of illustration and not limitation, FIG. 2 shows afirst prosthesis 20 having a first portion 20 a and a second portion 20b and a second prosthesis 30 having a first portion 30 a and a secondportion 30 b. As shown schematically, the beneficial agent distributionprofile includes a first local areal density of beneficial agent on oneof the first and second portions of one or both of the first prosthesisand the second prosthesis. For example and not by limitation, the firstportion 20 a of the first prosthesis 20 has half the local areal densityof beneficial agent as compared to the second portion 20 b of the firstprosthesis 20. The first portion 30 a of the second prosthesis 30,likewise, has half the local areal density of beneficial agent comparedto the second portion 30 b of the second prosthesis 30. In this manner,when the ends of two stents are superimposed or deployed in anoverlapping relationship 25 during a procedure, the local areal densityof beneficial agent along the interventional device 50 is controlled soas to be uniform. If desired, alternative concentrations can be providedon each portion so as to provide the desired effect in combination.

In accordance with the invention, as shown in FIG. 3, a controlled localareal density of beneficial agent is thus provided across a length ofthe interventional device 50 upon combination of the first prosthesishaving first portion 20 a and second portion 20 b with the secondprosthesis having first portion 30 a and second portion 30 b, as shownin FIG. 2. In particular, as shown in FIG. 3, the overlapping segment 25of first prosthesis 20 and the second prosthesis 30 has an equal localareal density of beneficial agent as compared to non-overlappingsegments 20 b and 30 b.

Alternatively, the beneficial agent distribution profile for theinterventional device may be controlled to include any of a variety ofdesired patterns. For example, the interventional device can have adecreased local areal density of beneficial agent on the distal andproximal ends of each prosthesis body, as noted above. This profile ishighly desirable in preventing adverse dosing of beneficial agent ifmultiple prostheses are placed in combination with each other but stillprovides for decreased dosage of the extreme ends of the interventionaldevice as a whole. Alternatively, as embodied herein, the beneficialagent distribution profile can provide a controlled local areal densitythat is uniform along the length of first prosthesis and secondprosthesis in combination, or multiple prostheses in combination.Alternatively, in accordance with the invention, the beneficial agentdistribution profile provides a controlled local areal density that isvaried along the length of the first prosthesis and the secondprosthesis in combination, or multiple prostheses in combination.

For illustration purposes, overlapping or nested prostheses, as shown inFIG. 3, can have beneficial agent distribution profiles such that thecontrolled local areal density of beneficial agent of a non-overlappingsegment is in fact greater than the controlled local areal density ofbeneficial agent of a overlapping segment. Similarly, the alternativecan also be true; that a overlapping segment is controlled to have agreater or different local areal density of beneficial agent than anon-overlapping segment. Advantageously, this feature also enablesselective dosing of beneficial agent to a targeted area when usingmultiple prostheses in combination, as well as a single prosthesisalone, Selective dosing of beneficial agent to a targeted area meansthat the beneficial agent can be applied to the prosthesis or prosthesesin combination such that the desired beneficial agent is loaded onto theprosthesis in a selective pattern so that the beneficial agent orbeneficial agents are released from the prosthesis in close proximity toa targeted location, Fluid jetting as previously described isparticularly preferred for selective dosing.

In accordance with the present invention, and as embodied schematicallyin FIG. 5, a bifurcated interventional device also can be provided,which includes a first prosthesis 20′ and a second prosthesis 30′ incombination to define an overlapping portion 50′ and non overlappingportions 20 b′, 30 b′. For purposes of illustration and not limitation,FIG. 4 shows a first prosthesis 20′ having a first portion 20 a′ and asecond portion 20 b′, and a second prosthesis 30′ having a first portion30 a′ and a second portion 30 b′. As shown for purpose of illustrationand not limitation, the beneficial agent distribution profile includes afirst local areal density of beneficial agent on one of the first andsecond portions of one or both of the first prosthesis 20′ and thesecond prosthesis 30′. For example, and not by limitation, the firstportion 20 a′ of the first prosthesis 20′ has half the local arealdensity of beneficial agent as compared to the second portion 20 b′ ofthe first prosthesis. The first portion 30 a′ of the second prosthesis30′ has half the local areal density of the second portion 30 b′ of thesecond prosthesis 30′. In accordance with the present invention, asshown in FIG. 5, a controlled local areal density of beneficial agent isthus provided across a length of the bifurcated interventional device 50upon combination of the first prosthesis having first portion 20 a′ andsecond portion 20 b′ with the second prosthesis having first portion 30a′ and second portion 30 b′, as shown in FIG. 4.

Another feature of the present invention includes applying a layer ofbase material on a selected portion of the prosthesis described above.The beneficial agent is loaded onto the base material layer according tothe methods described above. The base material layer preferably definesa pattern for loading the beneficial agent onto the prosthesis.

The present invention also encompasses, for any of the embodimentsdisclosed, the application of a rate-controlling topcoat over thebeneficial agent loaded prosthesis for further controlling or sustainingthe release of beneficial agent. The rate-controlling topcoat may beadded by applying a coating layer posited over the beneficial agentloaded prosthesis. The thickness of the layer is selected to providesuch control. Preferably, the overcoat is applied by fluid-jettechnology. Advantageously, fluid jetting an overcoat such as a polymerovercoat allows a thinner and more uniform layers. However otherconventional methods can be used such as other fluid-dispensers, vapordeposition, plasma deposition, spraying, or dipping, or any othercoating technique known in the art.

The present invention also provides a method for manufacturing aninterventional device for delivery of beneficial agent. This methodcomprises the steps of providing a first prosthesis to be deployedwithin a lumen; providing a second prosthesis configured to be deployedin an overlapping relationship with the first prosthesis, the firstprosthesis and the second prosthesis in combination defining at leastone non-overlapping segment and an overlapping segment; and loading thefirst prosthesis and the second prosthesis with beneficial agent toprovide a controlled local areal density along a length of the firstprosthesis and the second prosthesis in combination. The methoddescribed in detail above is preferred for such loading step.

The present invention also provides a method of delivering beneficialagent. In accordance with this method, as described in detail inconjunction with the description of the interventional device of thepresent invention above, the method comprising the steps of providing afirst prosthesis having a tubular body when deployed in a lumen;providing a second prosthesis having a tubular body when deployed in alumen; loading at least one of the first prosthesis and the secondprosthesis with beneficial agent; deploying the first prosthesis into alumen; deploying the second prosthesis into the lumen to define incombination with the first prosthesis at least one non-overlappingsegment and an overlapping segment; wherein the beneficial agent isloaded onto at least one of the first prosthesis and the secondprosthesis to provide a controlled local areal density of beneficialagent across a length of the first prosthesis and the second prosthesiswhen deployed. The method described in detail above is preferred forsuch loading step.

The present invention will be further understood by the examples setforth below, which are provided for purpose of illustration and notlimitation.

EXAMPLES Example 1 Jetting of Reactive Substances

The components of a commercial two-part epoxy formulation are mixed bythe jetting process and applied to a surface to form a coating. In aformulation manufactured by Buehler, Lake Bluff Ill., one part is aliquid “epoxide resin” that contains 4,4′ isopropylidenediphenolepichlorohydrin resin and butyl glycidyl ether. The second part is aliquid “hardener” that contains diethylene triamine, triethylenetetramine, and polyoxypropylenediamine. In the jetting process, onereagent jet system (A) is loaded with epoxide resin and a second jettingsystem (B) is loaded with hardener. The jets are aligned such that thedroplets emanating from each jet combine in midair and travel to thetarget device to form a crosslinked coating, after a curing time of 2-8hours. The volume of a droplet emanating from jet A is 5 times largerthan the volume of a droplet emanating from Jet B and the total numberof droplets dispensed from each jet are approximately equal.

Example 2 Jetting of Reactive Substances

The components of a commercial two-part epoxy formulation are mixed bythe jetting process and applied to a surface to form a coating. In a twopart commercial formulation manufactured by Buehler, Lake Bluff Ill.,one part is a liquid “epoxide resin” which contains 4,4′isopropylidenediphenol epichlorohydrin resin and butyl glycidyl ether.The second part is a liquid “hardener” that contains diethylenetriamine, triethylene tetramine, and polyoxypropylenediamine. In thejetting process, one reagent jet system (A) is loaded with epoxide resinand a second jetting system (B) is loaded with hardener. The jets arealigned such that the droplets emanating from each jet combine in midairand travel to the target device to form a crosslinked coating, after acuring time of 2-8 hours. The volume of a droplet emanating from jet Ais 4 times larger than the volume of a droplet emanating from Jet B andthe total number of droplets dispensed from each jet are approximatelyequal. This coating cures at a faster rate than the coating described inexample 1.

Example 3 Jetting of Reactive Substances

The components of a commercial two-part epoxy formulation are mixed bythe jetting process and applied to a surface to form a coating. In a twopart commercial formulation manufactured by Buehler, Lake Bluff Ill.,one part is a liquid “epoxide resin” which contains 4,4′isopropylidenediphenol epichlorohydrin resin and butyl glycidyl ether.The second part is a liquid “hardener” that contains diethylenetriamine, triethylene tetramine, and polyoxypropylenediamine. In thejetting process, one reagent jet system (A) is loaded with epoxide resinand a second jetting system (B) is loaded with hardener. The jets arealigned such that the droplets emanating from each jet combine in midairand travel to the target device to form a crosslinked coating, after acuring time of 2-8 hours. The volume of a droplet emanating from jet Ais approximately equal to the volume of a droplet emanating from Jet B,but the total number of droplets dispensed from jet A is 4 times morethan from jet B.

Example 4 Formation of a Crosslinked Network Containing BiologicallyActive Agents

One reagent jet system (A) is loaded with a liquid epoxide resin and asolubilized formulation of the drug, paclitaxel, 20% by weight withrespect to the epoxide resin. A second jetting system (B) is loaded withhardener similar to that described in example 1 combined with an equalweight or less of a biocompatible polymer. One example of such a speciesis a phosphorylcholine linked polymer of the general formulapoly(MPC_(w):LMA_(x):HPMA_(y):TSMA_(z)), where MPC is2-methacryoyloxyethylphosphorylcholine, LMA is lauryl methacrylate, HPMAis hydroxypropyl methacrylate and TSMA is trimethoxysilylpropylmethacrylate. This polymer is dissolved in a solvent such as chloroform.The jets are aligned such that the droplets from each jet combine inmidair and travel to the target device to form a crosslinked coatingentrapping the drug and polymer. The volume of a droplet emanating fromjet A is 5 times larger than the volume of a droplet emanating from jetB and the total number of droplets dispensed from each jet areapproximately equal. The coating is heated for 4 hours at 70 degrees C.to cause crosslinking of the phosphorylcholine-linked polymerpredominantly with itself by means of the trimethoxysilane groups, andsimultaneously accelerating the curing of the epoxide resin with thehardener.

Example 5 Formation of a Drug Microprecipate

One reagent jet system (A) is loaded with rapamycin dissolved inethanol. A second jetting system is loaded with water. The dropletvolume of one drop emanating from jet A is 50 picoliters and the dropletvolume of one drop emanating from Jet B is 150 picoliters. The jets arealigned such that the droplets from each jet combine in midair andtravel to the target device. During the droplet combination therapamycin will precipitate within the droplet and be deposited on thetarget surface as a microprecipitate.

Example 6 Loading of Drug onto a Polymer Base-Coated Coronary Stent

In a demonstration of feasibility, a stock jetting solution of 20 mg/mlABT-578+4 mg/ml phosphorylcholine-linked methacrylate polymer (PC) inisobutanol was prepared. A fluid jetting system manufactured by MicroFabTechnologies of Plano, Tex. was programmed to jet 75 micrograms of drugevenly over a 1.4×11 mm OC BiodivYsio stent to obtain an areal densityof 5 micrograms per linear mm. Jetting of 21,888 drops into a vialcontaining 10 ml of isobutanol gave 77 micrograms of ABT-578 asdetermined spectrophotometrically at 278 nm. Under these conditions, 1drop was 170-180 picoliters and had a diameter between 67 and 70microns. The stent contained a base coating of phosphorylcholine-linkedmethacrylate polymer (PC). It was mounted on a fixture that included amandrel that provided for controlled rotation (θ) about a central axiscoaxial with the stent and a stage that provided for lateral movement(X) along the axis of the stent. The motion control was set up to rotatethe stent a total of 720 degrees. A view orthogonal to the axis of therotating stent showed two possible tangential off-axis positions,approximately 50 microns inside a point tangent to the outer surface ofthe stent, one on each side of the rotation centerline, that providedrelatively few instances where a jet trajectory would not impinge on atleast one stent structural element. One of these off-axis positions wasfirst selected to start the drug loading. A mandrel mounted stent waspositioned so that the trajectory of jetted droplets would impinge onthe stent struts at this “off-axis” location. The motion controller wasset up to move the stent axially in the X direction and began its motionat a position where the jet trajectory was off the end of the stent. Themotion controller ramped up to a predetermined velocity and turned onthe fluid jetting head as soon as motion along the X axis reachedconstant velocity and the end of the stent struts were in a positiondirectly under the jet head. Every time the stent passed completelyunder the jet head along this off-axis path in the X direction, themotion controller would then ramp down the velocity, stop and rotate thestent 5 degrees. The linear direction was reversed and the next pass wasmade. After 360 degrees was reached, (72 passes) the table wastranslated approximately a distance equal to the internal diameter ofthe stent (1 ID) to the other off-axis position and 72 more passes weremade for an additional rotation of 360 degrees. Each stent was thusjetted twice to obtain its drug loading.

Seven (7) stents were loaded with drug. Observation of drug-loadedstents under a stereomicroscope indicated that no webbing occurredbetween stent struts and the surfaces were cosmetically smooth. Thestents were subsequently extracted into isobutanol for measurement ofthe drug obtained and the results are shown below.

Stent ABT-578 (micrograms) 1 70 2 72 3 69 4 69 5 53 6 61 7 60

The average loading obtained was 65 micrograms. The calculated captureefficiency was 84% based on the number of counted droplets of drugdispensed.

Example 7 Loading of PC-Coated Peripheral Stents by Reagent Jetting

In a similar feasibility demonstration experiment, a fluid jettingsystem manufactured by MicroFab Technologies of Plano, Tex. wasprogrammed to dispense 59,904 drops, approximately 3× that used for the11 mm OC stent. These peripheral vascular stents (SFA) were 5×30 mm andwere mounted on a larger sized rotation fixture. The stent matrix wasmuch more open than seen on the OC coronary stent; however, good captureefficiency was obtained.

Stent ABT-578 (micrograms) 1 187 2 176 3 185 average 183 Avg.

The jetter dispensed 211 micrograms of drug per stent, having a captureefficiency of 86%.

Example 8 Overcoating of a Drug-Loaded Stent with Polymer

A 10 mg/ml solution of phosphorylcholine-linked methacrylate polymer(PC) was made in isobutanol. A total of 288 passes along the axialdimension of the stent and over 1440 degrees of rotation under theconditions used in previous examples, produced an overcoat at 5micrograms per linear mm.

Example 9 Overcoating of a Drug-Loaded Stent with Polymer having aVariable Areal Density

A 10 mg/ml solution of phosphorylcholine-linked methacrylate polymer(PC) is made in isobutanol. The linear travel speed of the stent underthe jet head is programmed to be 50% slower during the beginning 25% ofthe stent length and the ending 25% of length. The jetting rate is notvaried over the length of the stent. A total of 288 passes along theaxial dimension of the stent and over 1440 degrees of rotation are made.Under these conditions, the stent obtains an increased amount of PC onboth ends of the stent compared to the middle regions.

Example 10 Drug-Loaded Stent having a Variable Areal Density of Drug

A stock jetting solution of 20 mg/ml ABT-578+4 mg/mlphosphorylcholine-linked methacrylate polymer (PC) in isobutanol isprepared. The linear travel speed of the stent under the jet head isprogrammed to be 50% faster during the beginning 25% of the stent lengthand the ending 25% of length. The jetting rate is not varied over thelength of the stent. A total of 144 passes along the axial dimension ofthe stent and over 720 degrees of rotation are made. Under theseconditions, the stent obtains a decreased amount of ABT-578 on both endsof the stent compared to the middle regions.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. For example, a charge-and-deflect dispenser can bereplaced with a drop-on-demand fluid jetter, or vice versa. Such changesand modifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and or methods of use of the invention, can bemade without departing from the spirit and scope thereof.

1. A system for loading beneficial agent onto a prosthesis for deliverywithin a lumen, the system comprising: a holder for supporting aprosthesis to be deployed within a lumen; a fluid-dispenser having adispensing element capable of dispensing beneficial agent in discretedroplets, each droplet having a controlled trajectory, the dispensingelement and the holder being movable relative to each other, saiddispensing element being positioned at a distance sufficient such thatthe dispensing element and prosthesis in the holder are separated by adistance that avoids simultaneous contact of the dispensing element andprosthesis by a discrete droplet; a driver for creating relativemovement between the dispensing element and the holder; a controller incommunication with the driver to define a dispensing path for dispensingdiscrete droplets of beneficial agent with the controlled trajectory ina raster format, the controller also in communication with thedispensing element to selectively dispense beneficial agent from thedispensing element to a predetermined portion of a prosthesis supportedby the holder along the dispensing path; and a beneficial agent detectorin communication with the controller configured to determine an amountof beneficial agent loaded on a prosthesis, the beneficial agentdetector being configured to be capable of detecting charge build-up onor current flow from the prosthesis to determine a corresponding amountof beneficial agent loaded to the prosthesis.
 2. The system of claim 1,further including a position detector to detect when the dispensingelement is aligned with the predetermined portion of the prosthesissupported by the holder.
 3. The system of claim 1, wherein the holderincludes a spindle made of a superelastic material.
 4. The system ofclaim 1, wherein the controller is programmed with the predeterminedportion of the prosthesis to which beneficial agent is to be dispensed.5. The system of claim 1, further comprising an identifiable markerconfigured to be loaded onto the prosthesis, wherein said beneficialagent detector in communication with the controller configured todetermine the amount of beneficial agent loaded on the prosthesisdetects the identifiable marker.
 6. The system of claim 1, wherein thecontroller is configured to instruct dispensing of the beneficial agentonto the prosthesis until the loaded amount of beneficial agent matchesa predetermined amount of beneficial agent.
 7. The system of claim 1,further comprising a charging electrode adjacent the fluid dispenserconfigured to add a charge to the discrete droplets.
 8. A system forloading beneficial agent onto a prosthesis for delivery within a lumen,the system comprising: a holder for supporting a prosthesis to bedeployed within a lumen; a fluid-dispenser having a dispensing elementcapable of dispensing beneficial agent in discrete droplets, eachdroplet having a controlled trajectory, the dispensing element and theholder being movable relative to each other, said dispensing elementbeing positioned at a distance sufficient such that the dispensingelement and prosthesis in the holder are separated by a distance thatavoids simultaneous contact of the dispensing element and prosthesis bya discrete droplet; a driver for creating relative movement between thedispensing element and the holder; a controller in communication withthe driver to define a dispensing path for dispensing discrete dropletsof beneficial agent with the controlled trajectory in a raster format,the controller also in communication with the dispensing element toselectively dispense beneficial agent from the dispensing element to apredetermined portion of a prosthesis supported by the holder along thedispensing path, wherein the controlled trajectory is controlled by thecontroller so as to not intersect a central axis of the prosthesis; anda beneficial agent detector in communication with the controllerconfigured to determine an amount of beneficial agent loaded on aprosthesis, the beneficial agent detector being configured to be capableof detecting the number of discrete droplets dispensed from thefluid-dispenser onto the prosthesis to determine a corresponding amountof beneficial agent loaded to the prosthesis.
 9. The system of claim 8,further including a position detector to detect when the dispensingelement is aligned with the predetermined portion of the prosthesissupported by the holder.
 10. The system of claim 8, wherein the holderincludes a spindle made of a superelastic material.
 11. The system ofclaim 8, wherein the controller is programmed with the predeterminedportion of the prosthesis to which beneficial agent is to be dispensed.12. A method for loading beneficial agent onto a prosthesis for deliverywithin a lumen, the method comprising: supporting on a holder aprosthesis to be deployed within a lumen; dispensing from a dispensingelement a beneficial agent in discrete droplets, each droplet having acontrolled trajectory; positioning the dispensing element at a distancefrom the holder, the distance sufficient to avoid simultaneous contactof the dispensing element and prosthesis by the dispensed discretedroplets; moving the holder and the dispensing element relative to eachother, the movement defining a dispensing path for the dispensing of thediscrete droplets of the beneficial agent with the controlled trajectoryin a raster format; and determining an amount of the beneficial agentdispensed on the prosthesis.
 13. The method of claim 12, wherein thedetermining of the amount of the beneficial agent dispensed on theprosthesis includes detecting a charge build-up on or current flow fromthe prosthesis.
 14. The method of claim 12, wherein the determining ofthe amount of the beneficial agent dispensed on the prosthesis includesdetecting the number of discrete droplets dispensed from the dispensingelement onto the prosthesis.
 15. The method of claim 12, wherein thecontrolled trajectory does not intersect a central axis of theprosthesis.